Journal article
Lysophosphatidic Acid Receptor Antagonism Protects against Diabetic Nephropathy in a Type 2 Diabetic Model
Journal of the American Society of Nephrology, v 28(11), pp 3300-3311
01 Nov 2017
PMID: 28739650
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Lysophosphatidic acid (LPA) functions through activation of LPA receptors (LPARs). LPA-LPAR signaling has been implicated in development of fibrosis. However, the role of LPA-LPAR signaling in development of diabetic nephropathy (DN) has not been studied. We examined whether BMS002, a novel dual LPAR1 and LPAR3 antagonist, affects development of DN in endothelial nitric oxide synthase-knockout
mice. Treatment of these mice with BMS002 from 8 to 20 weeks of age led to a significant reduction in albuminuria, similar to that observed with renin-angiotensin system inhibition (losartan plus enalapril). LPAR inhibition also prevented the decline in GFR observed in vehicle-treated mice, such that GFR at week 20 differed significantly between vehicle and LPAR inhibitor groups (
<0.05). LPAR inhibition also reduced histologic glomerular injury; decreased the expression of profibrotic and fibrotic components, including fibronectin,
-smooth muscle actin, connective tissue growth factor, collagen I, and TGF-
; and reduced renal macrophage infiltration and oxidative stress. Notably, LPAR inhibition slowed podocyte loss (podocytes per glomerulus ±SEM at 8 weeks: 667±40,
=4; at 20 weeks: 364±18 with vehicle,
=7, and 536±12 with LPAR inhibition,
=7;
<0.001 versus vehicle). Finally, LPAR inhibition minimized the production of 4-hydroxynonenal (4-HNE), a marker of oxidative stress, in podocytes and increased the phosphorylation of AKT2, an indicator of AKT2 activity, in kidneys. Thus, the LPAR antagonist BMS002 protects against GFR decline and attenuates development of DN through multiple mechanisms. LPAR antagonism might provide complementary beneficial effects to renin-angiotensin system inhibition to slow progression of DN.
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Details
- Title
- Lysophosphatidic Acid Receptor Antagonism Protects against Diabetic Nephropathy in a Type 2 Diabetic Model
- Creators
- Ming-Zhi Zhang - Vanderbilt Center for Kidney Disease, andXin Wang - Hypertension InstituteHaichun Yang - Vanderbilt UniversityAgnes B Fogo - Vanderbilt UniversityBrian J Murphy - Bristol-Myers Squibb (United States)Robert Kaltenbach - Bristol-Myers Squibb (United States)Peter Cheng - Bristol-Myers Squibb (United States)Bradley Zinker - Bristol-Myers Squibb (United States)Raymond C Harris - Hypertension Institute
- Publication Details
- Journal of the American Society of Nephrology, v 28(11), pp 3300-3311
- Publisher
- American Society of Nephrology (ASN)
- Grant note
- R01 DK056942 / NIDDK NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000414419000020
- Scopus ID
- 2-s2.0-85032624127
- Other Identifier
- 991021903120004721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- Web of Science research areas
- Urology & Nephrology